Copyright © American Psychiatric Publishing, Inc., or American Psychiatric Association, unless otherwise indicated in figure legend, All rights reserved.

Copyright © American Psychiatric Publishing, Inc., or American Psychiatric Association, unless otherwise indicated in figure legend, All rights reserved.

Most drugs circulate in the blood bound to plasma proteins, principally albumin or alpha-1-acid glycoprotein. Many psychotropic drugs are highly protein bound, frequently to a degree greater than 90%. Displacement of drug from plasma protein-binding sites may result from drug-drug interactions. This situation should lead to more unbound drug being available for distribution to peripheral tissues and interaction with receptor sites (see Figure 8-4). As a result, potentially greater pharmacological effects, either beneficial or detrimental, may be expected. However, there are few documented examples in which the above events occurred with psychoactive drugs and led to significant clinical consequences. Compensatory changes occur in the body to buffer the impact of drug-binding interactions (DeVane 2002). When plasma protein binding is restrictive regarding the drug's hepatic and/or renal elimination, the increased free drug concentration in plasma will be a transient effect as more free (non-protein-bound) drug becomes available to routes of elimination. Total (bound plus free) drug concentration in plasma will eventually return to a predisplacement value. The conclusion of several authoritative reviews is that plasma protein-binding displacement interactions are rarely a major source of variability in psychopharmacology (DeVane 2002; Greenblatt et al. 1982; Rolan 1994; Sellers 1979).


Drugs are eliminated or cleared from the body through renal excretion in an unchanged or conjugated form; through biotransformation, primarily in the liver, to polar metabolites; or through both of these mechanisms (see Figure 8-1). Clearance is defined as the volume of blood or other fluid from which drug is irreversibly removed per unit of time. Thus, clearance units are volume per time. Drug clearance is analogous to creatinine clearance by the kidney. From the blood that delivers drug to the liver, or any other eliminating organ, an extraction occurs as blood travels through the organ. Because drug extraction by the liver and other organs is rarely 100%, the portion that escapes presystemic elimination reaches the systemic circulation intact. Plasma protein binding, as mentioned above, can restrict the organ extraction process, depending on the specific drug. If a drug were to be completely extracted, then clearance would equal the blood flow to the organ. An average hepatic blood flow is 1,500 mL/minute. When drug is eliminated by additional organs, the total clearance is an additive function of all the individual organ clearances. Clearance values reported in excess of 1,500 mL/minute for many psychopharmacological drugs are reflective of presystemic elimination (DeVane 1994). When the drug dose and bioavailability are constant, then clearance is the pharmacokinetic parameter that determines the extent of drug accumulation in the body to a steady state. In contrast, elimination half-life is useful to reflect the rate, but not the extent, of drug accumulation.

Elimination half-life is defined as the time required for the amount of drug in the body, or drug concentration, to decline by 50%. This parameter is commonly determined after a single-dose pharmacokinetic study or after drug discontinuation in a multiple-dose study. In either situation, drug concentration decline in plasma can be followed by multiple blood sampling. Half-life is easily determined by graphical means or by inspection, as long as data are used from the terminal log-linear portion of the elimination curve (see Figures 8-2 and 8-3). Knowledge of a drug's elimination half-life is particularly useful for designing multiple-dosing regimens.

Multiple Dosing to Steady State

Multiple drug doses usually are required in the pharmacotherapy of mental illness. During a multiple-dosing regimen, second and subsequent drug doses are usually administered before sufficient time has elapsed for the initial dose to be completely eliminated from the body. This process results in drug accumulation, as illustrated in Figure 8-5. When drug elimination follows a linear or first-order process, the amount of drug eliminated over time is proportional to the amount of drug available for elimination (Gibaldi and Perrier 1975). Accumulation does not occur indefinitely; rather, it reaches a steady state. A steady state exists when the amount of drug entering the body is equal to the amount leaving the body. From a practical standpoint, this definition means that after a period of continuous dosing, the body retains a pool of drug molecules from several doses, and the drug eliminated each day is replaced by an equivalent amount of newly administered drug. The time required from the first administered dose to the point at which an approximate steady state occurs is equivalent to the total of four to five elimination half-lives. The same amount of time is required for a new steady state to be achieved after an increase or decrease in the daily dosing rate or for a drug to wash out of the body after dosing is discontinued (see Figure 8-5).

FIGURE 8-5. Accumulation of drug during multiple dosing.

FIGURE 8-5. Accumulation of drug during multiple dosing.

It takes four to five half-lives (4-5 ti/2) to achieve initial steady state (Cpss) on a constant dosage regimen, to achieve a new steady state after an increase in dosage, or to wash out drug from the body after discontinuation. The average steady-state concentration lies somewhere between the peaks and troughs of drug concentration during a dosage interval.

The term steady state is a misnomer in that a true drug steady state occurs only with a constant-rate intravenous infusion. Because of the concurrent processes of drug absorption, distribution, and elimination, drug concentration is constantly changing in plasma and tissues during an oral dosing regimen. A peak and a trough concentration occur within each dosage interval. The average steady-state concentration occurs somewhere between these extremes and is determined by the daily dose and the drug's total body clearance for that individual.

On reaching a steady-state concentration, the average concentration and the magnitude of the peaks and troughs may be manipulated according to established pharmacokinetic principles. Figure 8-6 shows the predicted plasma concentration changes based on drug doses given every 24 hours. The selected dose does not produce a high enough average steady-state concentration to reach the desired concentration range between an MEC and a concentration threshold associated with an increased risk of toxicity. By doubling the dose and keeping the dosage interval constant, the average steady-state concentration increases, but the magnitude of the peak and trough concentration difference also increases. These changes are consistent with the pharmacokinetic principles of superposition and linearity (Gibaldi and Perrier 1975).

FIGURE 8-6. Predicted plasma concentration changes from administering either a selected dose (D) every 24 hours

(D q24h), twice the dose every 24 hours (2D q24h), or the original dose every 12 hours (D q12h).

MEC = minimal effective concentration.

Linearity refers to maintaining a stable clearance across the usual dosage range. Within the linear dose range, the magnitude of a dosage increase results in a proportional change in steady-state concentration (see Figure 8-6). The magnitude of the dose change theoretically superimposes on the new peak and trough concentration. In Figure 8-6, doubling the daily dose results in an adequate average steady-state concentration, but the new peak and trough concentration values cause both an increased risk of toxicity and an inadequate concentration declining below the MEC for a portion of each dosage interval. An alternative is to increase the total daily dose and divide it into more frequent administrations. This is accomplished by administering the original dose every 12 hours instead of every 24 hours. The new average steady-state concentration remains within the desired range, and the differences between the peak and trough concentrations are reduced to an acceptable fluctuation.

Selection of a proper drug dosage regimen must consider both the amount of drug administered and the frequency of administration. Some drugs with half-lives long enough to be administered once daily may not be suitable for administration every 24 hours because toxicity may be precipitated by an excessive peak concentration in a single dose. Examples include lithium and clozapine. Once-daily dosing with lithium may produce gastrointestinal intolerance, and clozapine is dosed two or more times each day to avoid peak concentrations that might predispose to seizure activity. Bupropion was initially formulated to be dosed multiple times a day to avoid high peak concentrations in plasma for this same reason but reformulation into an extended-release tablet allows once-daily administration. When high peak concentration is tolerable, then the dosage interval can theoretically be extended beyond 1 day by giving larger amounts of drug in single doses less frequently. This principle applies to fluoxetine, which is available as a 90-mg capsule for once-weekly administration.

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